The solid-state structure of tricyclic antidepressants

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2021
Thesis identifier
  • T16520
Person Identifier (Local)
  • 201884123
Qualification Level
Qualification Name
Department, School or Faculty
  • The active pharmaceutical ingredient (API) is the biologically active molecule present in medication. These are most commonly formulated in the crystalline solid state due to the stability and advantageous material properties generally demonstrated. The pharmaceutical industry is interested in the stability of their APIs, because it is important that it does not change during production, while on the shelf or while in the recipient’s home. Solubility is another chemical property to control for maximum efficacy of a drug, as it aids bioavailability and distribution of the API to the desired site of action. Other important properties include melting point, mechanical hardness, and particle size. These properties have a large effect on the manufacturability of APIs as they affect processes such as grinding, mixing, and tabletting of solid products. Aqueous solubility, hygroscopicity, melting point, mechanical hardness and particle size are all examples of material properties of the bulk solid of solid form APIs. They strongly depend on the number, type and strength of intermolecular interactions in the solid and are therefore properties that can be controlled and altered by changing the solid-state structure without having to alter the API molecule. There are four main ways to alter the solid-state structure and change material properties without altering the API molecule. Altering the solid-state structure affects the number, type and strength of intermolecular interactions. The options to alter these interactions include the choice between amorphous and crystalline material, investigating the polymorphic landscape of the API, and co-crystal or salt formation. Salt formation was the route that was focussed on in this work. A salt screen was carried out on four closely related tricyclic antidepressants (TCAs): amitriptyline, nortriptyline, imipramine, and doxepin. All salt formation experiments were carried out exclusively in water in order to reduce the number of variables when comparing the resulting salt forms. A dataset of 29 newly elucidated crystal structures of TCA salt forms was generated. From this dataset a selection of nortriptyline salt forms was made for an apparent aqueous solubility study. The salt forms were selected due to the counterions being ‘Generally Regarded as Safe’ (GRAS) for use in pharmaceutical industry. The salt forms used were bromide, iodide, salicylate, tosylate, besylate and oxalate. A clear trend was observed, where the salt forms with halogen counterions showed a higher solubility than organic counterions. The most soluble salt form of nortriptyline was the chloride salt which was over 200 times more soluble than the salicylate salt, which was determined to be the least soluble. Structural analysis was carried out on the dataset which found that it would appear that all four TCA bases were much more likely to form Z’ > 1 structures than is normal. Only 8.8% of structures in the Cambridge Structural Database (CSD) were found to have a Z’ value larger than 1, compared to 52% of newly elucidated TCA crystal structures from this work. Three conformational motifs were investigated as possible causes for this increased likelihood of anomalous Z’ values. Three ring/chain conformations were identified, as well as three torsion angle α, and two torsion angle β options. Indeed, in structures with higher Z’ values, API molecules with mixtures of these conformations were observed. In addition, five of the Z’ = 1 TCA salt structures contained a cation site where all atoms of the cation were disordered. There is a chance that larger super cells or modulated structures have not been identified here and that these structures could be ordered with higher Z’ values. The structures were further analysed as part of a larger data set of tricyclic antidepressants obtained from the CSD by the crystal packing similarity tool in Mercury. Four isostructural groups were identified. It appeared that the four cation packing isostructural groups could be divided into two types. Groups 1 and 2 contained different API molecules and/or very diverse counterions, and different hydration states. This illustrated that cation packing can be isostructural even where the structures that make up the groups involve different cations, different anions, and different solvation states. Group 1 seems to be a group where identical cation packing is caused by the presence of the picrate anion. In contrast groups 3 and 4 contain pairs of closely related structures which differ only in the detail of the halide anion. Here isostructural packing of the cation is simply a subset of a larger structural similarity. The crystal packing similarity analysis was repeated with a dataset of 85 carbamazepine and dihydrocarbamazepine structures found in the CSD. Here, 12 isostructural groups were identified, that could be split into three types. Type 1, groups 1 and 2, consisted of polymorphic forms. In group 1, it may be possible that the structures were not isostructural, but indeed the same form, but solved in different crystals systems. For type 2, it appeared the groups were made up of structures where the co-formers were geometrically and functionally similar to each other. Here, isostructural packing of the cation is simply a subset of a larger structural similarity, as in the second type of TCA isostructural groups. Type 3 had less in common, the structures in each group contained either dissimilar co-formers or different solvation states. The driving force of isostructural packing here seemed to be the hydrogen bonding motif and the link between this and the structures in the type 3 groups being channel solvates. Overall, in most cases in groups 3 through 12, the unit cell dimensions were very similar. This could be further studied as a tool to predict isostructural forms.
Advisor / supervisor
  • Kennedy, Alan
Resource Type
  • Error on title page. Date of award is 2021.
Embargo Note
  • The digital version of this thesis is restricted to Strathclyde users only until the 01/07/2026